1. Field of the Invention
This invention relates to a novel condensed heterocyclic compounds which hive excellent gonadotropin-releasing hormone (GnRH) receptor antagonizing activity, as well as processes for producing the compounds, pharmaceutical compositions containing the compound, and medical uses for the pharmaceutical compositions.
The compounds of this invention also have calcium-antagonizing and monoamine-uptake inhibiting activities and are therefore useful as a prophylactic/therapeutic drug for acute and chronic central nervous system disorders and CNS-related diseases, such as dysmnesia.
2. Related Prior Art
Gonadotropin-releasing hormone (GnRH) is a deca-peptide consisting of 10 amino acids produced in the hypothalamus. It is known that this hormone regulates secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) through receptors which are considered to be present in the anterior lobe of the pituitary gland. GnRH thereby exhibits several physiological activities including induction of ovulation. Since an antagonist or agonist that is specific to such receptors is expected to regulate the hormonal activities of GnRH produced from the hypothalamus and control the secretion of anterior pituitary hormones (including LH or FSH, which inhibits the secretion of estrogen in female or testosteron in male) the prophylactic or therapeutic effect on anterior pituitary hormone-dependent diseases can be expected.
Since the discovery of gonadotropin-releasing hormone in 1971, a large number of its congeners have been synthesized in the expectation of agonistic or antagonistic activity. For example, leuprolerin acetate is a compound which has a higher affinity for GnRH receptors and is less easily metabolized than native GnRH.
Repeated administration ok leuprolerin acetate, which is 20 to 50-fold as active as native GnRH, causes the so-called receptor down regulation to decrease the release and production of gonadotropin-releasing hormone in the pituitary gland and, for example, reduce the response of the testis to gonadotropin and accordingly, reduce its testosterone-producing capacity to the castrated level or reduce estrogen-producing capacity in the ovary. It is known that the compound consequently shows an antitumor effect on hormone-dependent cancer, for example cancer of the prostate. In fact, leuprolerin acetate is in broad clinical use as a therapeutic agent for prostatic cancer, breast cancer and hystromyoma, as well as endometriosis, among other diseases.
However, these GnRH agonist are peptides which are poorly absorbed after oral administration and and therefore restricted in dosage form. Moreover, they develop agonistic activity transiently before the onset of efficacy following administration so that the steroidal sex hormone concentration in blood increases, sometimes cousing a transitory exacerbation such as ostealgia in some cases.
Accordingly, attempts are being made with the object of developing GnRH antagonists which provide therapeutic efficacy, but which are free of the above-mentioned side effects.
As compounds having such GnRH antagonizing activity, there is a list of known compounds such as cyclic hexapeptide derivatives (U.S. Pat. No. 4,659,691) and bicyclic peptide derivatives (J. Med. Chem., 36, 3265-3273, 1993), all of which have been developed with attention focused on the spatial configuration of GnRH. However, since these compounds are peptides, the perennial problems such as poor oral absorption and poor stability in the patient remain to be solved.
Meanwhile, synthesis of non-peptide compounds having GnRH receptor antagonizing activity has also been undertaken. U.S. Pat. No. 4,678,784 describes benzazepine compounds of the formula ##STR2## [wherein R.sup.1 represents an amino functional group of --NR.sup.3 R.sup.4, 4-morpholino, ##STR3## R.sup.2 represents hydrogen, alkoxy, alkyl, trifluoromethyl, halogen, nitro, hydroxy or dialkylamino;
R.sup.3 and R.sup.4 independently represent hydrogen, alkyl, or alkyl substituted by hydroxyl, halogen or alkoxy; PA1 m is equal to 0 or 1; PA1 n is equal to 0, 1 or 2; PA1 R.sup.5 represents hydroxyl, alkyl, halogen, carboxy, alkoxycarbonyl, or alkyl substituted by hydroxyl, halogen, alkoxy or phenyl; and PA1 R.sup.6 represents hydrogen, alkyl, carboxy, alkoxycarbonyl or phenyl; PA1 R.sup.7 represents hydrogen, alkyl, alkoxycarbonyl, or alkyl substituted by hydroxyl, halogen, alkoxy, phenoxy or alkoxycarbonyl]. Journal of Medical Chemistry 32, 2036-2038, 1989 describes and mentions that compounds of the formula ##STR4## wherein R represents ##STR5## have LHRH (luteinizing hormone-releasing hormone) antagonizing activity. PA1 X represents C.sub.2-4 alkylene; PA1 B represents di(lower)alkyl, piperidino, morpholino, pyrrolidino, N'-alkylpiperazino or pipecolino]. PA1 R.sup.2 represents ##STR9## (A represents alkylene; R.sup.5 and R.sup.6 independently represent alkyl or, taken together with the nitrogen atom, represent a 5- through 7-membered ring); PA1 R.sup.3 and R.sup.4 independently represent C.sub.1-4 alkoxy] as a cardiovascular drug is reported (U.S. Pat. No. 4,118,494), PA1 R.sub.4 represents hydrogen or C.sub.1-4 alkyl; PA1 A represents a bond, C.sub.1-6 alkylene or alkylidene; where PA1 Y is a bond, B represents C.sub.1-6 alkylene or alkylidene; where PA1 Y is O, S or NR.sup.5, B represents C.sub.2-6 alkylene; PA1 X represents CH or N; PA1 R.sub.5 represents hydrogen or C.sub.1-4 alkyl] as a therapeutic drug for angina pectoris and myocardial infarction which has intracellular calcium-antagonizing activity is reported (U.S. Pat. No. 5,238,939). PA1 Ar represents an aromatic group which may be substituted, PA1 R.sup.1 and R.sup.2 independently represent hydrogen atom, acyl group or hydrocarbon group (residue) which may be substituted or R.sup.1 and R.sup.2 taken together with the adjacent nitrogen atom represent a nitrogen-containing heterocyclic group, PA1 m represents an integer of 1 to 6, PA1 n represents an integer of 1 to 3, PA1 - - - - - represents a single bond or a double bond, PA1 X is --O-- or --NR.sup.3 -- (R.sup.3 represents hydrogen atom, acyl group or hydrocarbon group which may be substituted) where - - - - - is a single bond, or X is .dbd.N-- where - - - - - is a double bond, or a salt thereof. PA1 a) C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) PA1 b) C.sub.2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) PA1 c) C.sub.2-6 alkinyl (e.g. propargyl, ethinyl, butinyl, 1-hexinyl, etc.) PA1 a) C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.); cyclohexyl may be fused to a benzene ring which may be substituted by C.sub.1-4 alkyl or C.sub.1-4 alkoxy PA1 b) C.sub.6-14 aryl (e.g. phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-indenyl, 2-anthryl, etc.); phenyl is preferred PA1 c) C.sub.7-16 aralkyl (e.g. benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.); benzyl is preferred PA1 p represents an integer of 4 to 7, ##STR15## wherein Z represents --O--, &gt;CH--W or &gt;N--W (W represents (a) hydrogen atom or (b) a C.sub.6-14 aryl or C.sub.7-16 aralkyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino, or ##STR16## wherein ring D represents (a) a benzene ring or (b) 5- or 6-membered heteroaromatic group having 1 to 3 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 Y represents --CH.sub.2 --, --CO-- or --CH(OH)--, PA1 s and t each represents an integer of 1 to 3. PA1 Y.sup.a represents --CH.sub.2 -- or --CO--; PA1 - - - - - represents a single bond and X represents --O--; or PA1 - - - - - represents a single bond and X represents --NR.sup.3a -- in which R.sup.3a represents hydrogen atom or C.sub.1-6 alkyl group; PA1 p represents an integer of 4 to 7, ##STR19## wherein Z represents --O--, &gt;CH--W or &gt;N--W (W represents (a) hydrogen atom, (b) a C.sub.6-14 aryl or C.sub.7-16 aralkyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino or (c) a heterocyclic group which may be substituted), ##STR20## wherein ring D represents (a) a benzene ring or (b) a 5- or 6-membered heteroaromatic group having 1 to 3 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 Y represents --CH.sub.2 --, --CO-- or --CH(OH)--, PA1 s and t each represent.sub.s an integer of 1 to 3, or ##STR21## wherein ring D.sup.b represents a benzene ring which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 Y is --CH.sub.2 --, --CO-- or --CH(OH)--. PA1 p represents an integer of 4 to 7; PA1 the "benzene ring which may be substituted" mentioned just above is as defined hereinbefore. Among others, preferred are ##STR29## and so on. In the above formulae, G represents halogen (e.g. fluorine, chlorine, etc.), C.sub.1-6 alkyl (e.g. methyl, ethyl, isopropyl, etc.), or C.sub.1-6 alkoxy (e.g. methoxy, ethoxy, isopropoxy), etc., for instance. PA1 Y represents --CH.sub.2 --, --CO-- or --CH(OH)--, PA1 s and t each represents an integer of 1 to 3. PA1 Y.sup.a represents --CH.sub.2 or --CO--, among others, is used. PA1 Y represents --CH.sub.2 --, --CO-- or --CH(OH)--, PA1 s and t each represents an integer of 1 to 3. PA1 Y.sup.a represents --CH.sub.2 -- or --CO--. PA1 Ar.sup.a represents phenyl which may be substituted by 1 to 3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 W represents a C.sub.6-14 aryl (e.g. phenyl ) or C.sub.7-16 aralkyl (e.g. benzyl) group which may be substituted by 1 to 3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 m represents an integer of 1 to 6, PA1 - - - - - represents a single bond, PA1 X.sup.a stands for --O-- or --NR.sup.3a -- wherein R.sup.3a is hydrogen or C.sub.1-6 alkyl, or a salt thereof. PA1 Ar.sup.a represents phenyl which may be substituted by 1 to 3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 ring D.sup.a represents a benzene ring which may be substituted by 1 to 3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, PA1 Y.sup.a represents --CH.sub.2 -- or --CO--, PA1 m represents an integer of 1 to 6, PA1 - - - - - represents a single bond, PA1 X.sup.a stands for --O-- or --NR.sup.3a wherein R.sup.3a is hydrogen or C.sub.1-6 alkyl, or a salt thereof. PA1 L represents a leaving group; PA1 J represents lower (C.sub.1-6) alkyl, such as methyl or ethyl, in an inert solvent or mixed solvent, e.g. an ether solvent, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, an alcoholic solvent and/or an aromatic hydrocarbon solvent in the presence of a base at -20.degree. C. to 120.degree. C. for 5 minutes to 18 hours to provide an ester derivative (2).
Meanwhile, it is known that in cerebrovascular disorders or head injury, neuron-excitatory amino acids (among other factors) elevate intracellular Ca.sup.2+ concentration. This elevation of Ca.sup.2+ concentration causes activation of Ca.sup.2+ -dependent enzymes, which results in the over-excitment and consequent death of neurons, leading to aggravation of symptoms.
For the treatment of these diseases and specifically for controlling an excessive elevation of intracellular Ca.sup.2+ concentration, a variety of calcium channel blockers represented by dihydropyridines have been employed. However, these non-selective Ca.sup.2+ channel blockers act peripherally on the heart, blood vessels, etc. as well as the central nervous system. Moreover, some of them, such as flunarizine, have extrapyramidal side effects.
Recently, in dementia accompanied by shedding of neurofilaments, for example in Alzheimer's disease, the role of abnormal intracellular calcium ion concentration in the mechanism of the cytotoxicity of the etiologic factor .beta.-amyloid protein has been pointed out [Mark P. Mattson et al., Trends in NeuroScience, 16, 409]. Against the above background, it is now considered that a CNS-selective calcium ion antagonist would normalize the calcium ion homeostasis in the brain nerve cell and thereby show prophylactic and therapeutic efficacy for dementia.
WO92/06172 describes a piperidine derivative having CNS-selective calcium antagonistic activity.
Meanwhile, U.S. Pat. No. 2,759,936 describes, as an anticonvulsant, a compound of the formula ##STR6## [wherein R represents C.sub.1-6 alkyl;
A compound of the formula ##STR7## [wherein R.sup.1 and R.sup.2 independently represent hydrogen or C.sub.1-4 alkyl] is reported (U.S. Pat. No. 3,553,218),
a compound of the formula ##STR8## [wherein R.sup.1 represents hydrogen, C.sub.1-6 alkyl or phenyl;
a compound of the formula ##STR10## is reported (U.S. Pat. No. 4,650,884), and
a compound of the formula ##STR11## [wherein R.sub.1, R.sub.2 and R.sub.3 independently represent hydrogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, CF.sub.3 or methylenedioxy;